A scalable, cost-efficient and simple synthetic pathway towards potential bivalent opioid/dopamine receptor ligands was developed and optimized. Three novel compounds that contain both opioid and dopamine pharmacophores linked by the four methylene group chain were synthesized in 33, 35 and 39 % overall yield after a four-step synthetic route starting from three commercially available N-aryl piperazines. The anilino piperidine precursor was easily prepared in three steps, as previously published, starting from 4piperidone. The synthesis presented in this paper could be of interest for heterocyclic and general organic chemistry. The newly designed compounds possessing two pharmacophores, opioid and D 2 /D 3 , are potentially useful pharmacological probes. Of particular interest would be the simultaneous binding to both opioid and D 2 /D 3 receptors, and the resulting pharmacological responses may be useful for the further understanding of tolerance and dependence phenomena in opioid clinical use and/or abuse.

A series of sixteen novel substituted piperidines and (2-methoxyphenyl)piperazines were synthesized, starting from the key intermediates 1-(2-methoxyphenyl)-4-(piperidin-4-yl)piperazine and 1-(2-methoxyphenyl)-4-[(piperidin-4-yl)methyl]piperazine. Biological evaluation of the synthesized compounds was illustrated by seven compounds, of which 1-(2-methoxyphenyl)-4-{[1-(2-nitrobenzyl)piperidin-4-yl]methyl}piperazine had the highest affinity for the dopamine D 2 receptor. For all seven selected compounds, docking analysis was performed in order to establish their structure-to-activity relationship.

Herein, the synthesis and pharmacological evaluation of 13 novel compounds, designed as potential heterobivalent ligands for μ-opioid receptor (MOR) and dopamine D 2 receptors (D 2 DAR), are reported. The compounds consisted of anilido piperidine and N-aryl piperazine moieties, joined by a variable-length methylene linker. The two moieties represent MOR and D 2 DAR pharmacophores, respectively. The synthesis encompassed four steps, securing the final products in 28-42 % overall yields. The approach has a considerable synthetic potential, providing access to various related structures. Pharmacological tests involved in vitro competitive assay for D 2 DAR using [ 3 H] spiperon, as a standard radioligand, and in vivo antinociceptive tests for MOR. The measured dopamine affinities were modest to low, while antinociceptive activity was completely absent. Therefore, the compounds of the general structure prepared in this research are unlikely to be useful as opioid-dopamine receptor heterobivalent ligands.

A series of eight novel 5-substituted derivatives of benzimidazole was synthesized by condensation of the corresponding diamine with ethyl 4-[4--(2-chlorophenyl)piperazin-1-yl]butanoate in refluxing 4 M hydrochloric acid. In vitro antibacterial activity against ten strains, namely Bacillus subtilis, Clostridium sporogenes, Streptosporangium longisporum, Micrococcus flavus, Sarcina lutea, Staphylococcus aureus, Escherichia coli, Pseudomonas aeruginosa, Salmonella enteritidis and Proteus vulgaris and antifungal activity against two fungal strains, namely Candida albicans and Saccharomyces cerevisiae, were evaluated. Of all the compounds screened for activity, 2-{3-[4-(2-chlorophenyl)piperazin-1-yl]propyl}-5-iodo-1H-benzimidazole and 2-{3-[4-(2-chlorophenyl)piperazin-1-yl]propyl}-5-methyl-1H-benzimidazole were associated with higher antifungal activity than commercial drugs.

A total of 14 novel arylpiperazines were synthesized, and pharmacologically evaluated by measuring their affinities towards the D 2 dopamine receptor (DRD2) in a [ 3 H]spiperone competition assay. All the herein described compounds consist of a benzimidazole moiety connected to N-(2-methoxyphenyl)piperazine via linkers of various lengths. Molecular docking analysis and molecular dynamics simulations were performed on the DRD2-arylpiperazine complexes with the objective of exploring the receptor-ligand interactions and properties of the receptor binding site. The recently published crystal structure of DRD2 was used throughout this study. The major finding is that high affinity arylpiperazines must interact with both the orthosteric binding site and the extended binding pocket of DRD2 and therefore should contain a linker of 5 or 6 methylene groups long.

The synthetic route toward novel tricyclic, nitrogen-containing system is disclosed. Three novel compounds possessing structural features of 1,2,3,4-tetrahydroquinoxaline and decahydropyrido[3,4-b]pyrazine are synthesized starting from readily available precursors in six or seven steps, of which the last three or four steps respectfully are diastereoselective. Key reaction steps include N-acylation, Hofmann rearrangement and ring-closing Buchwald-Hartwig reaction. Compounds trans-8, cis-12 and trans-12 are synthesized in order to prove that this novel, tricyclic system can be functionalized with various groups. Synthetic significance of this heterocyclic system lies in the possibility for the orthogonal functionalization of three different amino groups, allowing fine structural tuning.